Methods for reducing the risk of an adverse teriflunomide and rosuvastatin interaction in multiple sclerosis patients

ABSTRACT

This invention relates to a method for managing the risk of an adverse interaction between teriflunomide and a substrate of breast cancer resistance protein (BCRP) and/or organic anion transporting polypeptide B1 and B3 (OATP1B1/B3).

FIELD OF THE INVENTION

This invention relates to a method for managing the risk of an adverseinteraction between teriflunomide and a substrate of breast cancerresistance protein (BCRP) and/or organic anion transporting polypeptideB1 and B3 (OATP1B1/B3).

BACKGROUND OF THE INVENTION

Teriflunomide is a novel oral disease-modifying therapy (DMT) for thetreatment of relapsing forms of multiple sclerosis (RMS). Teriflunomideblocks de novo pyrimidine synthesis, which inhibits the replication andfunction of activated (but not resting) lymphocytes.

The compound of (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4′-trifluoromethylphenyl)-amide (also known as teriflunomide,Formula I) is described in U.S. Pat. No. 5,679,709.

The use of teriflunomide for treating multiple sclerosis is described inU.S. Pat. No. 6,794,410. In vitro, teriflunomide inhibits of humanOATP1B1 with a half maximal inhibitory concentration (IC₅₀) of 7.1 μM,OATP1B3 with an IC₅₀ of 7.04 μM, OAT3 with an IC₅₀ of 1.3 μM and BCRPwith an IC₅₀ of 0.15 μM.

Rosuvastatin, a hypocholesterolemiant drug, is a selective, reversible,competitive inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA)reductase, the rate-limiting enzyme that converts HMG-CoA to mevalonateearly in the cholesterol pathway. Rosuvastatin is a substrate for NTCP,OATP1B1, OATPB1B3, organic anion transporter 3 (OAT3) and BCRPtransporters.

During an interaction study with teriflunomide, it is now found thatadministration of this active principle together with rosuvastatincauses an increase in the plasma concentration of rosuvastatin.

SUMMARY OF THE INVENTION

Accordingly, this invention relates to a method for managing the risk ofteriflunomide and rosuvastatin interaction in a patient having multiplesclerosis, particularly relapsing forms of multiple sclerosis, whereinrosuvastatin is co-administered with teriflunomide, comprisingadministering to the patient about 7 or 14 mg of teriflunomide daily,and administering to the patient rosuvastatin which is at the amount ofabout 50% of the normal dose of rosuvastatin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows plasma concentration of rosuvastatin followingadministration of rosuvastatin alone (Day 1) or with teriflunomide (Day12) (n≤15).

DETAILED DESCRIPTION OF THE INVENTION

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

“Administering a combination of teriflunomide and rosuvastatin” meansadministering both teriflunomide and rosuvastatin at the same time, inthe same day or within a period of 24 hours, particularly within aperiod of 12 hours.

“Co-administered” and “co-administering” means being administered oradministering at the same time, in the same day or within a period of 24hours, particularly within a period of 12 hours.

“Normal dose of rosuvastatin” means a dose of rosuvastatin that would berecommended for a patient to take or a doctor would prescribe thepatient to take if the patient is not taking teriflunomide concurrently.In one aspect, the normal dose of rosuvastatin is the dose approved byU.S. Food and Drug Administration, which is 5-40 mg daily. In anotheraspect, the normal dose of rosuvastatin is a dose that a patient hasbeen taking prior to the initiation of the treatment with teriflunomide.The dose of rosuvastatin is calculated based on its free acid form. Itshould be understood that rosuvastatin can be administered as apharmaceutically acceptable salt, particularly as rosuvastatin calcium,and the amount of salt administered should be adjusted accordingly.

“Patient” means a human.

“Pharmaceutically acceptable salts” as used herein means that the saltsof the compound of the present invention can be used in medicinalpreparations.

The present invention also relates to a method of providingteriflunomide wherein the teriflunomide is provided along withinformation indicating that it is useful for treating patients withmultiple sclerosis, particularly relapsing forms of multiple sclerosis,and in cases said patients also receive treatment of rosuvastatinwherein rosuvastatin is co-administered with teriflunomide, reducing thenormal dose of rosuvastatin by about 50% is recommended.

The present invention also relates to a method of promoting the use ofteriflunomide comprising conveying to a recipient at least one messagecomprising teriflunomide is useful for treating multiple sclerosis,particularly relapsing forms of multiple sclerosis, and in cases saidpatients also receive treatment of rosuvastatin wherein rosuvastatin isco-administered with teriflunomide, reducing the normal dose ofrosuvastatin by about 50% is recommended.

The present invention also relates to an article of manufacturecomprising

-   -   a) a packaging material:    -   b) teriflunomide, and    -   c) a label or package insert contained within the packaging        material indicating that teriflunomide is useful for treating        multiple sclerosis, particularly relapsing forms of multiple        sclerosis, and in cases said patients also receive treatment of        rosuvastatin wherein rosuvastatin is co-administered with        teriflunomide, reducing the normal dose of rosuvastatin by about        50% is recommended.

The present invention also relates to a package comprising teriflunomideand a label, said label comprising a printed statement which informs aprospective user that:

-   -   a) teriflunomide is indicated in patients with relapsing forms        of multiple sclerosis; and    -   b) in cases said patients also receive treatment of rosuvastatin        wherein rosuvastatin is co-administered with teriflunomide,        reducing the normal dose of rosuvastatin by about 50% is        recommended.

The present invention also relates to a method for administering acombination of teriflunomide and rosuvastatin to a patient havingmultiple sclerosis, particularly relapsing forms of multiple sclerosis,comprising administering to the patient about 7 or 14 mg ofteriflunomide daily, and co-administering to the patient rosuvastatinwhich is at the amount of about 50% of the normal dose of rosuvastatin.

The present invention may be better understood by reference to thefollowing non-limiting Example, which is exemplary of the invention. Itshould in no way be construed, however, as limiting the breath of thescope of the invention.

EXAMPLE

A single-center, open-label, 1-sequence, 2-period, 2-treatment crossoverstudy with a 5-day washout between periods was conducted in 15 healthymale subjects aged 18 to 45 to evaluate the effect of repeated doses ofteriflunomide on the pharmacokinetics (PK) of a single dose ofrosuvastatin 10 mg. All subjects received the following treatmentsduring each period:

-   -   1. Period 1: A single 10 mg dose of rosuvastatin was        administered in fasted state followed by a 5-day washout (from        Days 1 to 6). Day 6 corresponded to Day 1 of Period 2.    -   2. Period 2: A loading dose of 70 mg teriflunomide was        administered once a day for 4 days (Days 1 to 4), followed by 14        mg once a day for 8 days (Days 5 to 12) in fed conditions except        for Day 12. A single dose of 10 mg rosuvastatin was        co-administered with teriflunomide on Day 12 in fasted        conditions.

After last PK sample for rosuvastatin in Period 2 and discharge,cholestyramine was administered for at least 11 days in order toaccelerate the elimination of teriflunomide and until teriflunomideconcentration was ≤0.25 μg/mL.

The total duration of study participation for each subject was up to 3months, including the screening period and the cholestyramine washoutprocedure up to the end-of-study (EOS) visit.

-   -   1. Screening: −21 to −1 days before inclusion    -   2. Period 1: 5 days (from Days 1 to 6)    -   3. Period 2: 13 days+11 days of cholestyramine treatment (24        days)

The EOS visit (Day 35 to 42) was not complete until the subject'steriflunomide concentration was 0.25 μg/mL or lower.

Criteria for Evaluation:

The following PK parameters were calculated using noncompartmentalmethods from plasma rosuvastatin concentration obtained after singledose administration:

Primary:

Rosuvastatin: Area under the plasma concentration versus time curve(AUC) from time zero to the real time corresponding to the lastconcentration above the lower limit of quantitation, t_(last),(AUC_(last)) and area under the plasma concentration versus time curveextrapolated to infinity (AUC).

Secondary:

Rosuvastatin: Maximum plasma concentration (C_(max)) observed, time toreach maximum concentration (T max), t_(last), and terminal half-life(t_(1/2z)).

Teriflunomide: Plasma concentration before treatment administration onDays 10 to 13 during repeated dosing and plasma concentration duringcholestyramine treatment on Days 14, 15, 16, 20 and 25.

Pharmacokinetic sampling times and bioanalytical methods:

Sampling:

Rosuvastatin: Blood samples were collected at predose, 0.5, 1, 2, 3, 4,5, 6, 8, 10, 12, 24 and 36 hours postdose on Day 1 of Period 1 and Day12 of Period 2.

Teriflunomide: Blood samples were collected at predose on Days 10, 11,12, 13, 14, 15, 16, 20 and 25 in Period 2.

Bioanalytical methods: Rosuvastatin plasma concentrations weredetermined by a validated liquid chromatography couples with tandem massspectrometry (LC-MS/MS) method, with a LLOQ (lower limit ofquantification) of 50.1 pg/mL. Teriflunomide plasma concentrations weredetermined with a validated LC-MS/MS method with an LLOQ of 0.01 μg/mL.

Statistical Analysis:

Rosuvastatin PK parameters and teriflunomide C_(trough) (trough plasmaconcentration) were summarized with descriptive statistics for eachtreatment. For log transformed C_(max), AUC_(last) and AUC ofrosuvastatin, the effect of repeated oral doses of teriflunomide onsingle-dose rosuvastatin PK parameters was analyzed using a linearmixed-effect model to obtain estimates and 90% confidence intervals(Cls) for the ratio of geometric means of rosuvastatin co-administeredwith teriflunomide versus rosuvastatin alone.

Results:

It was found that there was an increase in mean rosuvastatin C_(max) andAUC (2.65- and 2.51-fold, respectively), following teriflunomide 70 mgQD for 4 days and 14 mg QD for 8 days. Mean±SD (CV %) [Geometric Mean]of the pharmacokinetic parameters of rosuvastatin with ratio estimatesand 90% Cls are shown in Table I below and FIG. 1.

Rosuvastatin + Treatment Rosuvastatin alone Teriflunomide Ratio ^(a)(90% CI) N 15 14 — C_(max) 3650 ± 1780 9340 ± 5110 2.65 (2.25, 3.12)(pg/mL) t_(max) ^(b) (h) 3.00 (2.00-5.00) 3.00 (2.00-3.00) — t_(1/2z)(h) 11.1 ± 2.99 12.3 ± 2.28 — AUC_(last) 31500 ± 16400 75400 ± 387002.52 (2.17, 2.91) (pg · h/mL) ^(c) AUC   34800 ± 17300 ^(d) 83000 ±41400 2.51 (2.16, 2.91) (pg · h/mL) ^(a) Teriflunomide + rosuvastatinversus rosuvastatin alone; ^(b) Median (min-Max); ^(c) Median t_(last)was 36 h for both treatment; ^(d) n = 14 due to AUC extrapolation >20%

Conclusion:

Teriflunomide is an inhibitor of BCRP and an OATP1B1/B3 substrate.Therefore, a 50% dose reduction of rosuvastatin is recommended whenco-administering with teriflunomide. For other substrates of BCRP (e.g.methotrexate, topotecan, sulfasalazine, daunorubicin, doxorubicin) andthe OATP family, especially HMG-Co reductase inhibitors (e.g.simvastatin, atorvastatin pravastatin, methotrexate, nateglinide,repaglinide, rifampin), concomitant administration of teriflunomideshould also be undertaken with caution. Patients should be monitoredclosely for signs and symptoms of excessive exposure to the drugs andreduction of the dose of these drugs should be considered.

We claim:
 1. A method of providing teriflunomide wherein theteriflunomide is provided along with information indicating that it isuseful for treating patients with relapsing forms of multiple sclerosis,and in cases said patients also receive treatment of rosuvastatinwherein rosuvastatin is co-administered with teriflunomide, reducing thedose of rosuvastatin to not exceeding 10 mg once daily is recommended.2. A method of promoting the use of teriflunomide comprising conveyingto a recipient at least one message comprising teriflunomide is usefulfor treating relapsing forms of multiple sclerosis, and in cases saidpatients also receive treatment of rosuvastatin wherein rosuvastatin isco-administered with teriflunomide, reducing the dose of rosuvastatin tonot exceeding 10 mg once daily is recommended.
 3. A method foradministering a combination of teriflunomide and rosuvastatin to apatient having multiple sclerosis, comprising administering to thepatient about 7 or 14 mg of teriflunomide daily, and co-administering tothe patient rosuvastatin at a dose that does not exceed 10 mg oncedaily.
 4. The method according to claim 3, wherein the patient hasrelapsing forms of multiple sclerosis.
 5. The method according to claim3, wherein rosuvastatin is co-administered with teriflunomide at thesame time.
 6. The method according to claim 4, wherein rosuvastatin isco-administered with teriflunomide at the same time.